title: Whole-exome sequencing reveals a rapid change in the frequency of rare functional variants in a founding population of humans.
abstract: Whole-exome or gene targeted resequencing in hundreds to thousands of individuals has shown that the majority of genetic variants are at low frequency in human populations. Rare variants are enriched for functional mutations and are expected to explain an important fraction of the genetic etiology of human disease, therefore having a potential medical interest. In this work, we analyze the whole-exome sequences of French-Canadian individuals, a founder population with a unique demographic history that includes an original population bottleneck less than 20 generations ago, followed by a demographic explosion, and the whole exomes of French individuals sampled from France. We show that in less than 20 generations of genetic isolation from the French population, the genetic pool of French-Canadians shows reduced levels of diversity, higher homozygosity, and an excess of rare variants with low variant sharing with Europeans. Furthermore, the French-Canadian population contains a larger proportion of putatively damaging functional variants, which could partially explain the increased incidence of genetic disease in the province. Our results highlight the impact of population demography on genetic fitness and the contribution of rare variants to the human genetic variation landscape, emphasizing the need for deep cataloguing of genetic variants by resequencing worldwide human populations in order to truly assess disease risk.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Ferran
authors.initials: F
authors.lastname: Casals
authors.forename: Alan
authors.initials: A
authors.lastname: Hodgkinson
authors.forename: Julie
authors.initials: J
authors.lastname: Hussin
authors.forename: Youssef
authors.initials: Y
authors.lastname: Idaghdour
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bruat
authors.forename: Thibault
authors.initials: T
authors.lastname: de Maillard
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Grenier
authors.forename: Jean-Cristophe
authors.initials: JC
authors.lastname: Grenier
authors.forename: Elias
authors.initials: E
authors.lastname: Gbeha
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Simon
authors.initials: S
authors.lastname: Girard
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Spinella
authors.forename: Mathieu
authors.initials: M
authors.lastname: Larivière
authors.forename: Virginie
authors.initials: V
authors.lastname: Saillour
authors.forename: Jasmine
authors.initials: J
authors.lastname: Healy
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernández
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Elie
authors.initials: E
authors.lastname: Haddad
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
mesh_terms: D002170:Canada; D003710:Demography; D004198:Disease Susceptibility; D059472:Exome / Q000235:genetics*; D005602:France; D005787:Gene Frequency; D005828:Genetics, Population; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D044465:White People / Q000235:genetics